With no effective therapy to date, the ongoing Type 1 diabetes (T1D) epidemic continues to be a major health problem. While immune therapeutics (ITs) hold great promise for the treatment of T1D, their inadequacy, serious toxicity, side effects, and morbidity have limited research efforts in the lifelong immunosuppression approach. This shortcoming has prompted investigators to search for alternative approaches. Targeted nanomedicine using polymeric nanoparticles (NPs) holds particular promise to enhance the delivery of ITs to treat T1D. This strategy can minimize the undesirable side effects of ITs by delivering them to diseased tissues, where they can undergo sustained release. In this multidisciplinary project, we aim to develop an innovative, targeted nanodelivery method for ITs for T1D. Although progress has been made in developing new formulations, a method of targeted delivery of NPs to specific tissue sites following systemic administration remains to be developed. The priming and activation of autoreactive T cells occurs in the pancreatic lymph nodes (PLNs), where naive T cells enter through lymph node (LN)-restricted vasculature known as high endothelial venules (HEVs) and encounter autoantigens from the pancreas presented by dendritic cells. Activated T cells traffic subsequently to the pancreas, causing insulitis and autoimmune diabetes. Notably, we have found that HEVs are also formed in the pancreas during the onset of diabetes in NOD mice. Our biodegradable polymeric NPs are coated with MECA79 IgM antibody by using maleimide-thiol chemistry (MECA79-MT-NP); MECA79 binds to peripheral node addressin (PNAd), a glycoprotein family expressed only by endothelial cells of the HEV. Here, we demonstrate for the first time the targeted delivery of MECA79-MT-NPs to the PLNs and pancreata of NOD mice following intravenous administration. We also provide human data that supports the clinical applicability of our delivery platform. Active targeted delivery to these sites has never been achieved in T1D. Moreover, our preliminary data shows that encapsulation of the IT anti-CD3 antibody inside our MECA79-MT-NPs results in more effective reversal of autoimmune diabetes in NOD mice than treatment with free anti-CD3. Our main hypothesis is that targeted delivery of anti-CD3 to the pancreatic lymph nodes (PLNs) and pancreata will increase its efficacy and decrease toxicity by reducing systemic dosing significantly. In Aim 1, we will examine and optimize the stability, binding efficacy, and biodistribution of MECA79-conjugated NPs (MECA79-NPs) by utilizing alkyne-azide chemistry to permit the attachment of the pentameric form of MECA79 to the NP (MECA79-AA-NP). In Aim 2, we will assess the clinical efficacy of encapsulating anti-CD3 inside the formulation of MECA79-NP with the optimized properties from Aim 1 in the reversal of autoimmune diabetes in NOD mice as well as elucidate the mechanisms by which our targeted therapy works. In Aim 3, we plan to test the binding capacity to the PLNs and pancreata of human T1D patients of our optimized MECA79-NPs. This multidisciplinary, collaborative approach will lay the groundwork for the introduction of an innovative, targeted delivery method of ITs for T1D.